Brown fat tissue in humans

Brown adipose tissue (BAT) is universally present in mammals. Thermal production in such tissue is physiologically important for maintaining temperature homeostasis and regulation of body mass in small-size homoiotherms. At present it is clearly established that unlike other large mammals, brown adipose in man and primates is retained throughout the whole postnatal othogenesis. Therefore, BAT appears as a possible effector of pharmacogenetic protection from human excessive adiposis. Systematic reserach of various functioning aspects of this unique organ of mammals were started abroad as early as 1960-es, and are actively developing at present. Domestic research of energy circulation physiology and of thermoregulation developed mostly outside the brown adipose tissue. Therefore, the principal objective of this publication is to draw attention of experimental and clinical researches to an intriguing aspect of the issue of energy circulation in humans--the issue of brown adipose functioning.     

Brown adipose tissue functions in humans

Human adults have functionally active BAT. The metabolic function can be reliably measured in vivo using modern imaging modalities (namely PET/CT). Cold seems to be one of the most potent stimulators of BAT metabolic activity but other stimulators (for example insulin) are actively studied. Obesity is related to lower metabolic activity of BAT but it may be reversed after successful weight reduction such as after bariatric surgery. This article is part of a Special Issue entitled Brown and White Fat: From Signaling to Disease.     

Brown adipose tissue in morbidly obese subjects

Background

Cold-stimulated adaptive thermogenesis in brown adipose tissue (BAT) to increase energy expenditure is suggested as a possible therapeutic target for the treatment of obesity. We have recently shown high prevalence of BAT in adult humans, which was inversely related to body mass index (BMI) and body fat percentage (BF%), suggesting that obesity is associated with lower BAT activity. Here, we examined BAT activity in morbidly obese subjects and its role in cold-induced thermogenesis (CIT) after applying a personalized cooling protocol. We hypothesize that morbidly obese subjects show reduced BAT activity upon cold exposure.

Methods and Findings

After applying a personalized cooling protocol for maximal non-shivering conditions, BAT activity was determined using positron-emission tomography and computed tomography (PET-CT). Cold-induced BAT activity was detected in three out of 15 morbidly obese subjects. Combined with results from lean to morbidly obese subjects (n = 39) from previous study, the collective data show a highly significant correlation between BAT activity and body composition (P<0.001), respectively explaining 64% and 60% of the variance in BMI (r = 0.8; P<0.001) and BF% (r = 0.75; P<0.001). Obese individuals demonstrate a blunted CIT combined with low BAT activity. Only in BAT-positive subjects (n = 26) mean energy expenditure was increased significantly upon cold exposure (51.5±6.7 J/s versus 44.0±5.1 J/s, P = 0.001), and the increase was significantly higher compared to BAT-negative subjects (+15.5±8.9% versus +3.6±8.9%, P = 0.001), indicating a role for BAT in CIT in humans.

Conclusions

This study shows that in an extremely large range of body compositions, BAT activity is highly correlated with BMI and BF%. BAT-positive subjects showed higher CIT, indicating that BAT is also in humans involved in adaptive thermogenesis. Increasing BAT activity could be a therapeutic target in (morbid) obesity.     

Brown adipose tissue thermogenesis: interdisciplinary studies

Energy expenditure for thermogenesis in brown adipose tissue (BAT) serves either to maintain body temperature in the cold or to waste food energy. It has roles in thermal balance and energy balance, and when defective, is usually associated with obesity. BAT can grow or atrophy; it is usually atrophied in obese animals. Control of BAT thermogenesis and growth is by the sympathetic nervous system, with integration of signals in the hypothalamus. Sensory nerves may also be involved. Understanding the control of growth and differentiation of BAT is important for discovering how to reactivate it is obesity. Studies on control of gene expression in BAT are concentrating on thermogenically important components such as the uncoupling protein (which allows BAT mitochondria to operate in a thermogenic uncoupled mode), lipoprotein lipase (which allows BAT to compete with white adipose tissue for dietary lipid), and thyroxine 5'-deiodinase (which allows endogenous triiodothyronine generation, part of the control of differentiation and growth of BAT). Differentiation of BAT cell precursors in culture has recently been achieved. BAT is present in adult humans and some anti-obesity drugs are targeted to stimulation of BAT thermogenesis. However, extrapolation to humans of results of studies of BAT requires the development of novel approaches to the noninvasive assessment of amount and function of human BAT.     

Brown adipose tissue activity controls triglyceride clearance

Brown adipose tissue (BAT) burns fatty acids for heat production to defend the body against cold and has recently been shown to be present in humans. Triglyceride-rich lipoproteins (TRLs) transport lipids in the bloodstream, where the fatty acid moieties are liberated by the action of lipoprotein lipase (LPL). Peripheral organs such as muscle and adipose tissue take up the fatty acids, whereas the remaining cholesterol-rich remnant particles are cleared by the liver. Elevated plasma triglyceride concentrations and prolonged circulation of cholesterol-rich remnants, especially in diabetic dyslipidemia, are risk factors for cardiovascular disease. However, the precise biological role of BAT for TRL clearance remains unclear. Here we show that increased BAT activity induced by short-term cold exposure controls TRL metabolism in mice. Cold exposure drastically accelerated plasma clearance of triglycerides as a result of increased uptake into BAT, a process crucially dependent on local LPL activity and transmembrane receptor CD36. In pathophysiological settings, cold exposure corrected hyperlipidemia and improved deleterious effects of insulin resistance. In conclusion, BAT activity controls vascular lipoprotein homeostasis by inducing a metabolic program that boosts TRL turnover and channels lipids into BAT. Activation of BAT might be a therapeutic approach to reduce elevated triglyceride concentrations and combat obesity in humans.     

Brown adipose tissue activity in hypocaloric-diet fed lactating rats

Hypocaloric diet feeding reduced the mitochondrial protein content and whole tissue GDP-binding in interscapular brown adipose tissue from both virgin and lactating rats. A reduction in brown fat lipoprotein lipase activity was also detected in underfed virgin and lactating animals. These results indicate that lactation in the rat, even though it produces a reduction in brown fat activity, does not impair the capacity of the tissue to respond to a diminished caloric intake by lowering its activity further.     

Brown adipose tissue thermogenesis contributes to fentanyl-evoked hyperthermia

Mu-opioid receptor activation increases body temperature and affects cardiovascular function. In the present study, fentanyl was administered intravenously [100 mug/kg (300 nmol/kg) iv] and intracerebroventricularly [3.4 mug (10 nmol) in 10 microl icv] in urethane-chloralose-anesthetized, artificially ventilated rats. Increases in brown adipose tissue (BAT) sympathetic nerve activity (SNA) (peak, +326% of control), BAT temperature (peak, +0.8 degrees C), renal SNA (peak, +146% of control), and heart rate (HR; peak, +32 beats/min) produced by intravenous fentanyl were abolished by premamillary transection of the neuraxis but were mimicked by intracerebroventricular administration of fentanyl, which also increased arterial pressure (AP; peak, +12 mmHg). Pretreatment with the opioid antagonist naloxone (100 nmol in 10 microl icv) eliminated the intracerebroventricular fentanyl-evoked responses. Microinjection of glycine (0.5 M, 60 nl) to inhibit local neurons in the rostral raphe pallidus (RPa) selectively reversed the intracerebroventricular fentanyl-evoked increases in BAT SNA and HR, while the fentanyl-evoked excitation in RSNA, the pressor responses, and the tachycardic responses were reversed by inhibition of neurons in the rostral ventrolateral medulla (RVLM). Prior inhibition of neurons in the dorsomedial hypothalamus eliminated the intracerebroventricular fentanyl-evoked increases in BAT SNA, BAT temperature, and HR, but not those in RSNA or AP. These results indicate that activation of central mu-opioid receptors with fentanyl can elicit BAT thermogenesis and cardiovascular stimulation through excitation of the sympathetic outflows to BAT, kidney, and heart. Activation of neurons in the rostral RPa and RVLM are essential for the increases in BAT thermogenesis and renal sympathoexcitation, respectively, induced by activation of central mu-opioid receptors. BAT thermogenesis could contribute to fentanyl-evoked hyperthermia, particularly in infants where BAT plays a significant role in thermoregulation.     

Brown adipose tissue thermogenesis in T3-treated rats.

T4 treatment results in an inactivation of brown adipose tissue (BAT) which has been attributed to a reduced need of thermoregulatory heat production. Since T3 formation in brown adipocytes is governed by a type II T4 5'-deiodinase which is inhibited by T4, we analyzed the possibility that results obtained by T4 treatment were due to a lack of T3 in the tissue. Hyperthyroidism was induced in adult rats by administration of T3 (50 micrograms/kg body weight daily s.c.). Euthyroid and hyperthyroid rats were maintained at 23 degrees C or exposed at 6 degrees C for 3 weeks. Hyperthyroid rats at 23 degrees C showed an increase in BAT mass and in DNA and total lipids contents; however, BAT thermogenic activity was depressed. BAT from cold-exposed hyperthyroid rats showed the same mass and DNA content than at 23 degrees C, but it showed an increase in thermogenic activity, this increase being lower than in cold-exposed euthyroid rats. We conclude that high levels of T3 in BAT do not stimulate the thermogenic activity of the tissue. On the contrary, they inhibit it in response to lower requirements of facultative thermogenesis, both at 23 degrees C and at 6 degrees C.     

Brown adipose tissue: Updates in cellular and molecular biology

Brown adipose tissue (BAT) is mainly composed of adipocytes, it is highly vascularized and innervated, and can be activated in adult humans. Brown adipocytes are responsible for performing non-shivering thermogenesis, which is exclusively mediated by uncoupling protein (UCP) -1 (a protein found in the inner mitochondrial membrane), the hallmark of BAT, responsible for the uncoupling of the proton leakage from the ATP production, therefore, generating heat (i.e. thermogenesis). Besides UCP1, other compounds are essential not only to thermogenesis, but also to the proliferation and differentiation of BAT, including peroxisome proliferator-activated receptor (PPAR) family, PPARgamma coactivator 1 (PGC1)-alpha, and PRD1-BF-1-RIZ1 homologous domain protein containing protein (PRDM) -16. The sympathetic nervous system centrally regulates thermogenesis through norepinephrine, which acts on the adrenergic receptors of BAT. This bound leads to the initialization of the many pathways that may activate thermogenesis in acute and/or chronic ways. In summary, this mini-review aims to demonstrate the latest advances in the knowledge of BAT.     

Brown adipose tissue function in short-chain acyl-CoA dehydrogenase deficient mice

Brown adipose tissue is a highly specialized organ that uses mitochondrial fatty acid oxidation to fuel non-shivering thermogenesis. In mice, mutations in the acyl-CoA dehydrogenase family of fatty acid oxidation genes are associated with sensitivity to cold. Brown adipose tissue function has not previously been characterized in these knockout strains. Short-chain acyl-CoA dehydrogenase (SCAD) deficient mice were found to have increased brown adipose tissue mass as well as modest cardiac hypertrophy. Uncoupling protein-1 was reduced by 70% in brown adipose tissue and this was not due to a change in mitochondrial number, nor was it due to decreased signal transduction through protein kinase A which is known to be a major regulator of uncoupling protein-1 expression. PKA activity and in vitro lipolysis were normal in brown adipose tissue, although in white adipose tissue a modest increase in basal lipolysis was seen in SCAD−/− mice. Finally, an in vivo norepinephrine challenge of brown adipose tissue thermogenesis revealed normal heat production in SCAD−/− mice. These results suggest that reduced brown adipose tissue function is not the major factor causing cold sensitivity in acyl-CoA dehydrogenase knockout strains. We speculate that other mechanisms such as shivering capacity, cardiac function, and reduced hepatic glycogen stores are involved.